The proposed research is designed to elucidate the role of hepatic subcellular organelles in the assembly and secretion of lipoproteins. Our approach is to interfere with these normal physiological processes in order to elucidate the pathological effects of such derangements on cellular function and to perturb the subsequent metabolism of plasma lipoproteins. An analysis of the process of lipoprotein assembly and secretion using correlative biochemical, immunochemical and ultrastructural techniques can provide important information concerning the role of specific lipoproteins in hepatic lipid transport and the pathological effects on the cell when the normal secretion of these lipoproteins is deranged. The studies will, therefore, utilize experimental models to investigate: the role of subcellular organelles in hepatic lipoprotein biosynthesis; the importance of glycoprotein synthesis in the secretion of lipoproteins by the liver; the effect of experimental inhibition of the enzyme lecithin:cholesterol acyltransferase which regulates plasma cholesterol esterification on the metabolism of cholesterol and lipoproteins. The long-term objective of all of these studies is not merely the definition of the normal physiological processes involved in lipid transport but to gain an understanding of the normal control mechanisms involved in lipoprotein production and the effects of modifying or modulating these controls in order to better appreciate human derangements in lipoprotein metabolism. This is of particular importance in understanding the pathogenesis of atherosclerotic disease and other diseases characterized by disturbances in lipid and lipoprotein metabolism and, therefore, may provide information leading to the development of rational forms of therapy. BIBLIOGRAPHIC REFERENCES: Sabesin, S.M., Hawkins, H.L., Kuiken, L. and Ragland, J.B.: Abnormal plasma lipoproteins and lecithin:cholesterol acyltransferase deficiency in alcoholic liver disease. Gastroenterology, 72:510-518, 1977. Sabesin, S.M., Clark, S.B., and Holt, T.R.: Ultrastructural features of regional differences in chylomicron secretion by rat intestine. Exp. Mol. Pathol., In press, April, 1977.